Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program

Daniel Taliun, Daniel N. Harris, Michael D. Kessler, Jedidiah Carlson, Zachary A. Szpiech, Raul Torres, Sarah A. Gagliano Taliun, André Corvelo, Stephanie M. Gogarten, Hyun Min Kang, Achilleas N. Pitsillides, Jonathon LeFaive, Seung-been Lee, Xiaowen Tian, Brian L. Browning, Sayantan Das, Anne-Katrin Emde, Wayne E. Clarke, Douglas P. Loesch, Amol C. Shetty, Thomas W. Blackwell, Albert V. Smith, Quenna Wong, Xiaoming Liu, Matthew P. Conomos, Dean M. Bobo, François Aguet, Christine Albert, Alvaro Alonso, Kristin G. Ardlie, Dan E. Arking, Stella Aslibekyan, Paul L. Auer, John Barnard, R. Graham Barr, Lucas Barwick, Lewis C. Becker, Rebecca L. Beer, Emelia J. Benjamin, Lawrence F. Bielak, John Blangero, Michael Boehnke, Donald W. Bowden, Jennifer A. Brody, Esteban G. Burchard, Brian E. Cade, James F. Casella, Brandon Chalazan, Daniel I. Chasman, Yii- Der Ida Chen, Michael H. Cho, Seung Hoan Choi, Mina K. Chung, Clary B. Clish, Adolfo Correa, Joanne E. Curran, Brian Custer, Dawood Darbar, Michelle Daya, Mariza Andrade, Dawn L. DeMeo, Susan K. Dutcher, Patrick T. Ellinor, Leslie S. Emery, Celeste Eng, Diane Fatkin, Tasha Fingerlin, Lukas Forer, Myriam Fornage, Nora Franceschini, Christian Fuchsberger, Stephanie M. Fullerton, Soren Germer, Mark T. Gladwin, Daniel J. Gottlieb, Xiuqing Guo, Michael E. Hall, Jiang He, Nancy L. Heard-Costa, Susan R. Heckbert, Marguerite R. Irvin, Jill M. Johnsen, Andrew D. Johnson, Robert Kaplan, Sharon L. R. Kardia, Tanika Kelly, Shannon Kelly, Eimear E. Kenny, Douglas P. Kiel, Robert Klemmer, Barbara A. Konkle, Charles Kooperberg, Anna Köttgen, Leslie A. Lange, Jessica Lasky-Su, Daniel Levy, Xihong Lin, Keng-Han Lin, Chunyu Liu, Ruth J. F. Loos, Lori Garman, Robert Gerszten, Steven A. Lubitz, Kathryn L. Lunetta, Angel C. Y. Mak, Ani Manichaikul, Alisa K. Manning, Rasika A. Mathias, David D. McManus, Stephen T. McGarvey, James B. Meigs, Deborah A. Meyers, Julie L. Mikulla, Mollie A. Minear, Braxton D. Mitchell, Sanghamitra Mohanty, May E. Montasser, Courtney Montgomery, Alanna C. Morrison, Joanne M. Murabito, Andrea Natale, Pradeep Natarajan, Sarah C. Nelson, Kari E. North, Jeffrey R. O’Connell, Nicholette D. Palmer, Nathan Pankratz, Gina M. Peloso, Patricia A. Peyser, Jacob Pleiness, Wendy S. Post, Bruce M. Psaty, D. C. Rao, Susan Redline, Alexander P. Reiner, Dan Roden, Jerome I. Rotter, Ingo Ruczinski, Chloé Sarnowski, Sebastian Schoenherr, David A. Schwartz, Jeong-Sun Seo, Sudha Seshadri, Vivien A. Sheehan, Wayne H. Sheu, M. Benjamin Shoemaker, Nicholas L. Smith, Jennifer A. Smith, Nona Sotoodehnia, Adrienne M. Stilp, Weihong Tang, Kent D. Taylor, Marilyn Telen, Timothy A. Thornton, Russell P. Tracy, David J. Berg, Ramachandran S. Vasan, Karine A. Viaud-Martinez, Scott Vrieze, Daniel E. Weeks, Bruce S. Weir, Scott T. Weiss, Lu-Chen Weng, Cristen J. Willer, Yingze Zhang, Xutong Zhao, Donna K. Arnett, Allison E. Ashley-Koch, Kathleen C. Barnes, Eric Boerwinkle, Stacey Gabriel, Richard Gibbs, Kenneth M. Rice, Stephen S. Rich, Edwin K. Silverman, Pankaj Qasba, Weiniu Gan, George J. Papanicolaou, Deborah A. Nickerson, Sharon R. Browning, Michael C. Zody, Sebastian Zöllner, James G. Wilson, L. Adrienne Cupples (), Cathy C. Laurie (), Cashell E. Jaquish (), Ryan D. Hernandez (), Timothy D. O’Connor () and Gonçalo R. Abecasis ()
Additional contact information
Daniel Taliun: University of Michigan School of Public Health
Daniel N. Harris: University of Maryland School of Medicine
Michael D. Kessler: University of Maryland School of Medicine
Jedidiah Carlson: University of Michigan
Zachary A. Szpiech: Pennsylvania State University
Raul Torres: University of California, San Francisco
Sarah A. Gagliano Taliun: University of Michigan School of Public Health
André Corvelo: New York Genome Center
Stephanie M. Gogarten: University of Washington
Hyun Min Kang: University of Michigan School of Public Health
Achilleas N. Pitsillides: Boston University School of Public Health
Jonathon LeFaive: University of Michigan School of Public Health
Seung-been Lee: University of Washington
Xiaowen Tian: University of Washington
Brian L. Browning: University of Washington
Sayantan Das: University of Michigan School of Public Health
Anne-Katrin Emde: New York Genome Center
Wayne E. Clarke: New York Genome Center
Douglas P. Loesch: University of Maryland School of Medicine
Amol C. Shetty: University of Maryland School of Medicine
Thomas W. Blackwell: University of Michigan School of Public Health
Albert V. Smith: University of Michigan School of Public Health
Quenna Wong: University of Washington
Xiaoming Liu: University of South Florida
Matthew P. Conomos: University of Washington
Dean M. Bobo: Icahn School of Medicine at Mount Sinai
François Aguet: The Broad Institute of MIT and Harvard
Christine Albert: Massachusetts General Hospital
Alvaro Alonso: Emory University
Kristin G. Ardlie: The Broad Institute of MIT and Harvard
Dan E. Arking: Johns Hopkins University School of Medicine
Stella Aslibekyan: University of Alabama
Paul L. Auer: University of Wisconsin Milwaukee
John Barnard: Cleveland Clinic
R. Graham Barr: Columbia University Medical Center
Lucas Barwick: The Emmes Corporation
Lewis C. Becker: Johns Hopkins University
Rebecca L. Beer: National Institutes of Health
Emelia J. Benjamin: Boston University School of Medicine
Lawrence F. Bielak: University of Michigan School of Public Health
John Blangero: University of Texas Rio Grande Valley School of Medicine
Michael Boehnke: University of Michigan School of Public Health
Donald W. Bowden: Wake Forest School of Medicine
Jennifer A. Brody: University of Washington
Esteban G. Burchard: University of California, San Francisco
Brian E. Cade: Harvard Medical School
James F. Casella: Johns Hopkins University
Brandon Chalazan: University of British Columbia
Daniel I. Chasman: Brigham and Women’s Hospital
Yii- Der Ida Chen: The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center
Michael H. Cho: Brigham and Women’s Hospital
Seung Hoan Choi: The Broad Institute of MIT and Harvard
Mina K. Chung: Cleveland Clinic
Clary B. Clish: The Broad Institute of MIT and Harvard
Adolfo Correa: University of Mississippi Medical Center
Joanne E. Curran: University of Texas Rio Grande Valley School of Medicine
Brian Custer: Vitalant Research Institute
Dawood Darbar: University of Illinois at Chicago
Michelle Daya: University of Colorado Anschutz Medical Campus
Mariza Andrade: Mayo Clinic
Dawn L. DeMeo: Brigham and Women’s Hospital
Susan K. Dutcher: Washington University
Patrick T. Ellinor: The Broad Institute of MIT and Harvard
Leslie S. Emery: University of Washington
Celeste Eng: University of California, San Francisco
Diane Fatkin: Victor Chang Cardiac Research Institute
Tasha Fingerlin: Center for Genes, Environment and Health
Lukas Forer: Medical University of Innsbruck
Myriam Fornage: University of Texas Health Science Center at Houston
Nora Franceschini: University of North Carolina
Christian Fuchsberger: University of Michigan School of Public Health
Stephanie M. Fullerton: University of Washington School of Medicine
Soren Germer: New York Genome Center
Mark T. Gladwin: University of Pittsburgh
Daniel J. Gottlieb: VA Boston Healthcare System
Xiuqing Guo: The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center
Michael E. Hall: University of Mississippi Medical Center
Jiang He: Tulane University
Nancy L. Heard-Costa: Framingham Heart Study
Susan R. Heckbert: University of Washington
Marguerite R. Irvin: University of Alabama at Birmingham
Jill M. Johnsen: University of Washington
Andrew D. Johnson: Framingham Heart Study
Robert Kaplan: Albert Einstein College of Medicine
Sharon L. R. Kardia: University of Michigan School of Public Health
Tanika Kelly: Tulane University
Shannon Kelly: Vitalant Research Institute
Eimear E. Kenny: Icahn School of Medicine at Mount Sinai
Douglas P. Kiel: The Broad Institute of MIT and Harvard
Robert Klemmer: University of Michigan School of Public Health
Barbara A. Konkle: University of Washington
Charles Kooperberg: Fred Hutchinson Cancer Research Center
Anna Köttgen: Johns Hopkins University
Leslie A. Lange: University of Colorado at Denver
Jessica Lasky-Su: Harvard Medical School
Daniel Levy: Boston University School of Medicine
Xihong Lin: Harvard University
Keng-Han Lin: University of Michigan School of Public Health
Chunyu Liu: Boston University School of Public Health
Ruth J. F. Loos: Icahn School of Medicine at Mount Sinai
Lori Garman: Oklahoma Medical Research Foundation
Robert Gerszten: Beth Israel Deaconess Medical Center
Steven A. Lubitz: Massachusetts General Hospital
Kathryn L. Lunetta: Boston University School of Public Health
Angel C. Y. Mak: University of California, San Francisco
Ani Manichaikul: University of Virginia
Alisa K. Manning: Harvard Medical School
Rasika A. Mathias: Johns Hopkins University
David D. McManus: University of Massachusetts Medical School
Stephen T. McGarvey: Brown University
James B. Meigs: The Broad Institute of MIT and Harvard
Deborah A. Meyers: University of Arizona
Julie L. Mikulla: National Institutes of Health
Mollie A. Minear: National Institutes of Health
Braxton D. Mitchell: University of Maryland School of Medicine
Sanghamitra Mohanty: St David’s Medical Center
May E. Montasser: University of Maryland School of Medicine
Courtney Montgomery: Oklahoma Medical Research Foundation
Alanna C. Morrison: University of Texas Health Science Center at Houston
Joanne M. Murabito: Boston University School of Medicine
Andrea Natale: St David’s Medical Center
Pradeep Natarajan: Harvard Medical School
Sarah C. Nelson: University of Washington
Kari E. North: University of North Carolina
Jeffrey R. O’Connell: University of Maryland School of Medicine
Nicholette D. Palmer: Wake Forest School of Medicine
Nathan Pankratz: University of Minnesota
Gina M. Peloso: Boston University School of Public Health
Patricia A. Peyser: University of Michigan School of Public Health
Jacob Pleiness: University of Michigan School of Public Health
Wendy S. Post: Johns Hopkins University
Bruce M. Psaty: University of Washington
D. C. Rao: Washington University in St Louis
Susan Redline: Harvard Medical School
Alexander P. Reiner: University of Washington
Dan Roden: Vanderbilt University Medical Center
Jerome I. Rotter: The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center
Ingo Ruczinski: Johns Hopkins Bloomberg School of Public Health
Chloé Sarnowski: Boston University School of Public Health
Sebastian Schoenherr: Medical University of Innsbruck
David A. Schwartz: University of Colorado at Denver
Jeong-Sun Seo: Seoul National University Bundang Hospital
Sudha Seshadri: Framingham Heart Study
Vivien A. Sheehan: Emory University School of Medicine
Wayne H. Sheu: Taichung Veterans General Hospital Taiwan
M. Benjamin Shoemaker: Vanderbilt University Medical Center
Nicholas L. Smith: University of Washington
Jennifer A. Smith: University of Michigan School of Public Health
Nona Sotoodehnia: University of Washington
Adrienne M. Stilp: University of Washington
Weihong Tang: University of Minnesota
Kent D. Taylor: The Lundquist Institute for Biomedical Innovation, Harbor-UCLA Medical Center
Marilyn Telen: Duke University
Timothy A. Thornton: University of Washington
Russell P. Tracy: University of Vermont Larner College of Medicine
David J. Berg: University of Southern California
Ramachandran S. Vasan: Boston University School of Medicine
Karine A. Viaud-Martinez: Illumina Laboratory Services, Illumina Inc
Scott Vrieze: University of Minnesota
Daniel E. Weeks: University of Pittsburgh
Bruce S. Weir: University of Washington
Scott T. Weiss: Harvard Medical School
Lu-Chen Weng: Massachusetts General Hospital
Cristen J. Willer: University of Michigan
Yingze Zhang: University of Pittsburgh
Xutong Zhao: University of Michigan School of Public Health
Donna K. Arnett: University of Kentucky
Allison E. Ashley-Koch: Duke University Medical Center
Kathleen C. Barnes: University of Colorado Anschutz Medical Campus
Eric Boerwinkle: University of Texas Health Science Center at Houston
Stacey Gabriel: The Broad Institute of MIT and Harvard
Richard Gibbs: Baylor College of Medicine Human Genome Sequencing Center
Kenneth M. Rice: University of Washington
Stephen S. Rich: University of Virginia
Edwin K. Silverman: Brigham and Women’s Hospital
Pankaj Qasba: National Institutes of Health
Weiniu Gan: National Institutes of Health
George J. Papanicolaou: National Institutes of Health
Deborah A. Nickerson: University of Washington
Sharon R. Browning: University of Washington
Michael C. Zody: New York Genome Center
Sebastian Zöllner: University of Michigan School of Public Health
James G. Wilson: University of Mississippi Medical Center
L. Adrienne Cupples: Boston University School of Public Health
Cathy C. Laurie: University of Washington
Cashell E. Jaquish: National Institutes of Health
Ryan D. Hernandez: University of California, San Francisco
Timothy D. O’Connor: University of Maryland School of Medicine
Gonçalo R. Abecasis: University of Michigan School of Public Health

Nature, 2021, vol. 590, issue 7845, 290-299

Abstract: Abstract The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)1. In the first 53,831 TOPMed samples, we detected more than 400 million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400 million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.

Date: 2021
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DOI: 10.1038/s41586-021-03205-y

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